Method of making (1S, 4R)-1-azabicyclo[2.2.1]heptan-3-one and (1R, 4S), 1-azabicyclo[2.2.1]heptan-3-one

ABSTRACT

Racemic (±)-1-azobicyclo[2.2.1]heptan-3-one may be efficiently resolved into its (1S,4R)- and (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one isomers by formation of di-p-toluoyl hemitartrate salts by combination with di-p-toluoyl-L-tartaric acid and di-p-toluoyl-D-tartaric acid, respectively. Selective crystallization using one of the di-p-toluoyltartaric acids in less than stoichiometric amount in a suitable solvent mixture allows isolation of the desired isomer as its respective di-p-toluoyl hemitartrate in high isomeric purity. The isolated hemitartrates are storage stable and may be used as such in the preparation of pharmaceuticals and other biologically active compounds, or may be used to provide the free base of the respective 1-azabicyclo[2.2.1]heptan-3-one isomer.

This application is a 371 of PCT/US98/01413 filed Jan. 27, 1998, and isbased on provisional application No. 60/036,285 filed Jan. 27, 1997.

TECHNICAL FIELD

This invention relates to a method of obtaining(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, the di-p-toluoyl-L-tartaricacid hemisalt of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one and the di-p-toluoyl-D-tartaricacid hemisalt of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one from(±)-1-azabicyclo[2.2.1]heptan-3-one.

BACKGROUND OF THE INVENTION

(±)-1-Azabicyclo[2.2.1]heptan-3-one as well as enantiomerically pureforms of 1-azabicyclo[2.2.1]heptan-3-one and mixtures thereof have beenshown to be useful in the preparation of compounds which are useful aspharmaceutical agents. See, e.g., U.S. Pat. No. 5,514,812, incorporatedherein by reference. Certain compounds formed from enantiomerically pureforms of 1-azabicyclo[2.2.1]heptan-3-one are muscarinic agonists,rendering them useful as pharmaceutical agents in the area of cognitiondisorders, as disclosed, for example, in U.S. Pat. No. 5,346,911;European Published Applications EP 414,394 A2; EP 427,390 A2; EP 402,056A2; EP 307,142 A1; and various publications, e.g. H. Tecle et al.,BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, 5, 631-636, (1995) ; H.Tecle, et al., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, 5, 637-642,(1995), all incorporated herein by reference.

In order to be commercially viable, an efficient and cost-effective,large scale process for preparing substantially enantiomerically pureforms of 1-azabicyclo[2.2.1]heptan-3-one isomers is needed. JakobBoelsterli et al., HELV. CHIM. ACTA, 75, 507-12 (1992) prepared(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one by oxidation of(1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol. See also, U.S. Pat. No.5,346,911. This route involves the formation of racemic1-azabicyclo[2.2.1]heptan-3-exo-ol in four or more steps. The racemicalcohol is then resolved using D-tartaric acid (unnatural tartaric acid)by formation of a 1 to 1 salt. (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-olis then freed from the D-tartaric acid and recrystallized several times.The (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol is then oxidized (Swernoxidation) at low temperatures (-60° C.) to give(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The crude(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one is then isolated as thehydrochloride salt and recrystallized. A similar reaction sequence iscarried out using L-tartaric acid in order to obtain(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one.

Although the route disclosed by the prior art provides (1S,4R)- and(1R,4S)-azabicyclo[2.2.1]heptan-3-ones as the respective hydrochloridesalts in high enantiomeric purity, the process is difficult to conducton large-scale for the following reasons: 1) the process is long,involving at least five steps in addition to the resolution and freealcohol formation steps, 2) the process utilizes a low temperatureoxidation step (-60° C.) which requires specialized equipment on amanufacturing scale, and 3) the process relies upon a potentiallyhazardous oxidation step. In the latter respect, see, e.g., L.Bretherick, "Bretherick's Handbook of Reactive Chemical Hazards", FourthEdition, Butterworths, Boston, Mass., pp. 299-300 (1990). The knownpotential alternative to the hazardous oxidation step, utilized in theformation of racemic 1-azabicyclo[2.2.1]heptan-3-one as reported by Spryet al., J. ORG. CHEM, 34, 3674 (1969), does not work as well, andutilizes chromic acid, a toxic and environmentally problematic substanceand a known carcinogen. See, e.g., Budavari, S., Ed., THE MERCK INDEX,Twelfth Edition, p. 375, Merck, Whitehouse Station, N.J. (1996). Itwould be desirable to provide an efficient and economical process forobtaining substantially enantiomerically pure(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one and(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. It would be further desirableto provide these substantially enantiomerically pure isomers in astable, easily stored form.

SUMMARY OF THE INVENTION

The present invention provides an efficient means for obtaining(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, the stable easily storeddi-p-toluoyl-L-tartaric acid hemisalt of(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, and the stable easily storeddi-p-toluoyl-D-tartaric acid hemisalt of(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. It is readily conducted on ascale suitable for commercial use and involves at least 2 fewer stepsthan the published procedure. It further avoids the use of lowtemperature reactions, the use of a potentially hazardous oxidationstep, and the use of toxic chromic acid. Unexpectedly, the resolutionprocedure of the present invention provides a salt in which both of thecarboxylic acid groups of the respective resolving agents,di-p-toluoyl-L-tartaric acid or di-p-toluoyl-D-tartaric acid, areefficiently utilized in the formation of a 2 to 1 salt (hemisalt).Therefore, the process may be carried out using less resolving agentthan expected, resulting in a more economical process. In addition, theresolution procedure was unexpectedly found to give a stable, easilystored salt which can be converted to compounds of pharmaceuticalinterest without the need for prior isolation of the1-azabicyclo[2.2.1]heptan-3-one free base. The process comprisescombining (±)-1-azabicyclo[2.2.1]heptan-3-one anddi-p-toluoyl-L-tartaric acid in an appropriate solvent or solventmixture, allowing a precipitate to form, and collecting the solidprecipitated (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one hemisalt; orcombining (±)-1-azabicyclo[2.2.1]heptan-3-one anddi-p-toluoyl-D-tartaric acid in an appropriate solvent or solventmixture, allowing a precipitate to form, and recovering the precipitated(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one hemisalt. The respectivehemisalts (hemitartrates) may be stored as the hemisalt, or may bereacted with base to liberate the respective1-azabicyclo[2.2.1]heptan-3-one free base.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides the compounds: ##STR1## and a process fortheir preparation. (±)-1-azabicyclo[2.2.1]heptan-3-one may be preparedby known methods. See, e.g., Saunders et al., J. CHEM. SOC., CHEM.COMMUN., 24, 1618-9 (1988) ; Street et al., J. MED. CHEM. 33 2690-7(1990); European Published Patent Application EP 307,140 A1; EuropeanPublished Patent Application EP 414,394 A2; U.S. Pat. Nos. 5,217,975 and5,405,853; and European Published Patent Application EP 239,309 A2.(1S,4R)-1-Azabicyclo[2.2.1]heptan-3-one may be obtained from(±)-1-azabicyclo[2.2.1]heptan-3-one by combining racemic(±)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric acid ina protic or aprotic solvent or a mixture of protic or aprotic solvents;allowing a precipitate to form; and collecting the solid precipitate.The (1R,4S) isomer, (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one may beobtained from (±)-1-azabicyclo[2.2.1]heptan-3-one by combining(±)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-D-tartaric acid ina similar solvent or solvent mixture; allowing a precipitate to form;and collecting the solid precipitate. The reaction sequence forpreparation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-L-tartaric acid hemisalt and the corresponding free base,(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, is illustrated in accordancewith Scheme I below: ##STR2##

Scheme I

Scheme I illustrates a method for obtaining the di-p-toluoyl-L-tartaricacid hemisalt of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one from(±)-1-azabicyclo[2.2.1]heptan-3-one and for obtaining(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one from(±)-1-azabicyclo[2.2.1]heptan-3-one, the method comprising combining(±)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric acid ina protic or aprotic solvent or a mixture of protic or aprotic solvents;allowing a precipitate to form; and collecting the solid precipitatecorresponding to the di-p-toluoyl-L-tartaric acid hemisalt, andobtaining the free base by treatment with base. Scheme II reflects theidentical reaction sequence employing di-p-toluoyl-D-tartaric acid,whereby the di-p-toluoyl-D-tartaric acid hemisalt of(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one precipitates, from which thefree base (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one can be liberated.##STR3##

Scheme II

(±)-1-Azabicyclo[2.2.1]heptan-3-one can be resolved in accordance withthe present invention, i.e. the enantiomers separated, by selectivecrystallization with di-p-toluoyl-L-tartaric acid ordi-p-toluoyl-D-tartaric acid. (±)-1-Azabicyclo[2.2.1]heptan-3-one andeither (but not both) di-p-toluoyl-L-tartaric acid ordi-p-toluoyl-D-tartaric acid can be combined in solvents such asalcohols, ethers, esters, nitrites, mixtures of water and one or morealcohols, or mixtures of the aforementioned solvents. Examples ofsuitable alcohols include methanol, ethanol, n-propanol, isopropylalcohol, n-butanol, tert-butanol, and the like. Examples of suitableethers include diethyl ether, tert-butylmethyl ether, tetrahydrofuranand the like. Examples of suitable esters include methyl acetate, ethylacetate, isopropyl acetate, n-butyl acetate and the like. Examples ofsuitable nitrites include acetonitrile and the like. This list ofsolvents is illustrative and not limiting.

The suitability of a given solvent mixture may be readily assessed byadding (±)-1-azabicyclo[2.2.1]heptan-3-one and the particulardi-p-toluoyltartaric acid to the solvent mixture in the presence of seedcrystals of the respective hemitartrate salt. The precipitate can becollected and its quantity gravimetrically determined. Its purity can beassessed by HPLC using a chiral adsorbent. Such determinations areeasily performed by one skilled in the art. A solvent or solvent mixturewhich provides the desired purity, generally greater than 90% pure withrespect to the 1-azabicyclo[2.2.1]heptan-3-one isomers, and insufficient quantity (i.e. solubility is not too great), is a "selectivecrystallization-effective" solvent or solvent mixture as that term isused herein.

In general, the (1S,4R) isomer of 1-azabicyclo[2.2.1]heptan-3-oneprecipitates from the solution as approximately a 2 to 1 salt withdi-p-toluoyl-L-tartaric acid. A shortage of di-p-toluoyl-L-tartaric acidis preferably used in order that a product of high isomeric purity isobtained. Additional di-p-toluoyl-L-tartaric acid can be used in thecrystallization if a lower isomeric purity can be tolerated in theproduct. For example, the stoichiometry relative to di-p-toluoyltartaricacid is calculated based on the formation of the hemitartrate of thedesired isomer. Thus, 1 mol of racemic(±)-1-azabicyclo[2.2.1]heptan-3-one will contain 0.5 mol of the (1S,4R)isomer, or 0.5 mol-equivalent. Since the hemitartrate is formed in thereaction, 1 mol of di-p-toluoyl-L-tartaric acid represents 2mol-equivalents. Thus, for 1 mol (±)-1-azabicyclo[2.2.1]heptan-3-one,the stoichiometric amount of di-p-toluoyl-L-tartaric acid required toform the respective hemitartrate is 0.25 mol. However, it is generallydesirable to enhance the isomeric purity of the product. Enhancedisomeric purity may be achieved by utilizing from 50% to about 95% ofthe stoichiometric amount of the respective di-p-toluoyltartaric acid,more preferably from about 70% to 90% of this amount. Thus, to resolve 1mol of the racemic mixture of (±)-1-azabicyclo[2.2.1]heptan-3-one andisolate a substantially pure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-onedi-p-toluoyl-hemi-(L)-tartrate, approximately 0.20 mol ofdi-p-toluoyl-L-tartaric acid may be used. Similarly, when isolating the(1R,4S) isomer, di-p-toluoyl-D-tartaric acid is employed, the (1R,4S)isomer precipitating as a 2:1 salt (hemisalt; hemitartrate) with theresolving agent.

Removal of the respective di-p-toluoyltartaric acid from thehemitartrate salt to give the respective isomer-enriched1-azabicyclo[2.2.1]heptan-3-one free base can be accomplished by methodswell known to those skilled in the art, or by partitioning the saltbetween an acidic aqueous phase, such as aqueous hydrochloric acid, andan organic phase, such as tert-butylmethyl ether. The acidic aqueousphase may then be concentrated, and rendered basic by the addition of abase such as potassium carbonate, sodium hydroxide or the like.Extraction of the aqueous phase with an appropriate solvent such asethyl acetate, methylene chloride, chloroform, or the like followed byremoval of the solvent from the organic extracts by distillation givesthe enriched (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one.

Following separation of the desired isomer as its respectivedi-p-toluoyl hemitartrate salt by precipitation from solution, a second,somewhat less pure crop of crystals may be collected by addition offurther amounts of the particular di-p-toluoyltartaric acid to themother liquor and cooling to a temperature sufficient to precipitatefurther amounts of the hemisalt. In general, this temperature is lowerthan that of the first precipitation (crystallization). Bothprecipitations are advantageously promoted through addition of seedcrystals of the desired isomerically pure product.

If it is desired to isolate the non-precipitated isomer, a quantity ofthe requisite di-p-toluoyltartaric acid may be added to the solution andprecipitate collected as before. For example, if di-p-toluoyl-L-tartaricacid is added to (±)-1-azabicyclo[2.2.1]heptan-3-one to precipitate thedi-p-toluoyl-L-hemitartrate of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,this precipitation may be followed by addition of a further amount ofdi-p-toluoyl-L-tartaric acid to recover a second crop of somewhat lesspure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The (1R,4S) isomerenriched 1-azabicyclo[2.2.1]heptan-3-one may then be isolated from themother liquor by methods well known to those skilled in the art.

It is entirely feasible, and desired, to combine mixtures havingenriched concentrations of the desired isomer for further purification.For example, mixtures containing the hemitartrate of(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in isomeric purities of lessthan 90% may be combined and recrystallized, or may be converted to therespective free base, and reprecipitated with di-p-toluoyl-L-tartaricacid, to obtain the hemitartrate in high purity, typically greater than95%. The mother liquor will still contain further (1S,4R)-isomer and canbe combined with other similar mother liquor fractions for laterpurification. In this manner, expensive starting materials are conservedin an economical fashion. The di-p-toluoyl-L-tartaric acid anddi-p-toluoyl-D-tartaric acid resolving agents can themselves beseparated, i.e. after liberation of the 1-azabicyclo[2.2.1]heptan-3-onefree base, and purified by conventional techniques.

It was highly surprising that the use of the (L) and (D)di-p-toluoyltartric acids facilitated such an efficient resolution ofthe (1S,4R) and (1R,4S) isomers of (±)-1-azabicyclo[2.2.1]heptan-3-one.It was even more surprising that the respective hemitartrates wereformed, allowing the resolution of 2 mols of1-azabicyclo[2.2.1]heptan-3-one for only 1 mol of resolving agent. Notonly is the process efficient, but most importantly, it is capable ofpractice in commercial scale quantities, all without use of lowtemperature, potentially dangerous oxidation, or use of environmentallyquestionable and carcinogenic oxidizing agents such as chromiumtrioxide.

The inventive process allows the isolation of the desired isomers asstorage stable salts. Thus, also provided by the present invention arethe novel compounds: ##STR4##

It is contemplated that the compounds of the present method can be foundor isolated in the form of hydrates or solvates as well as thehemitartrates per se, all of which are considered to fall within thescope of the present invention.

The examples below are intended to illustrate specific embodiments ofthe invention and are not intended to limit the scope of thespecification, including the claims, in any manner.

EXAMPLES Example 1 Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-L-tartaric acid hemisalt

Di-p-toluoyl-L-tartaric acid (20.0 kg, 51.8 mol) was dissolved inacetonitrile (55 kg) and heated to 40-43° C. with agitation. Seedcrystals of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-L-tartaric acid hemisalt (0.1 kg) were added.(±)-1-Azabicyclo[2.2.1]heptan-3-one (28.8 kg dissolved in 26.1 kg ethylacetate, 259 mol) was dissolved in acetonitrile (115 kg) and heated to40-43° C. The (±)-1-azabicyclo[2.2.1]heptan-3-one solution was added tothe di-p-toluoyl-L-tartaric acid solution over a period of 2 hours. Themixture was cooled to 20-25° C. over a period of 1 hour. The solidproduct was collected by filtration and washed with cold acetonitrile(40 kg). The product was dried under reduced pressure (2 mmHg) at 40-45°C. for 21-22 hours to give 27.0 kg of product. Chiral HPLC: (ChiralpakAD (Chiral Technologies, Inc., Exton, Pa.) Hexane/IPA/DEA, 70:30:0.1,(solution concentration: ˜40 mg sample dissolved in ˜5 mL isopropylalcohol containing 5 drops of diethylamine)) enantiomeric purity 97.2%(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. ¹ H-NMR (DMSO, 200 MHZ): δ 9.6(s (broad), 1H), 7.87 (d, 2H, J=8.1 Hz), 7.35 (d, 2H, J=8.1 Hz), 5.69(s, 1H), 3.28-2.99 (m, 4H), 2.92-2.81 (m, 3H), 2.38 (s, 3H), 2.19-2.02(m, 1H), 1.71-1.58 (m, 1H). ¹³ C-NMR (DMSO, 50 MHZ): δ 213.2, 168.5,164.8, 143.8, 129.3, 129.2, 126.7, 72.4, 62.1, 58.0, 50.9, 47.4, 24.2,21.1. IR (KBr): 700.0, 757.9, 1112.7, 1128.2, 1172.5, 1268.9, 1342.2,1612.2, 1718.3, 1772.3, 2989.1, 3008.4 cm⁻¹.

Additional material may be obtained from the filtrate using thefollowing procedure:

Di-p-toluoyl-L-tartaric acid (7.5 kg, 19 mol) was dissolved inacetonitrile (7.5 kg) at 20-25° C. The di-p-toluoyl-L-tartaric acidsolution was added to the acetonitrile filtrate. Seed crystals of(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt (0.05 kg) were added. The mixture was cooled to 0-5° C. andstirred for 1-2 hours. The solid was collected by filtration and washedwith cold acetonitrile (20 kg). The solid was dried under reducedpressure (4 mmHg) at 40-45° C. for 19 hours to give 6.1 kg of crudeproduct. Chiral HPLC: 91.1% (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. Thecrude product (6.1 kg, 20 mol) was dissolved in methanol (6.1 kg) andadded to a mixture of isopropyl alcohol (45 L) and(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt seed crystals (0.04 kg) at 20-25° C. The mixture was stirred at20-25° C. for 1 hour. The solid was collected by filtration and washedwith isopropyl alcohol (15 L). The product was dried under reducedpressure (3 mmHg) at 40-45° C. for 20-21 hours to give 4.6 kg ofproduct. Chiral HPLC: 98.4% (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one.

Example 2 Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-L-tartaric acid hemisalt

(±)-1-Azabicyclo[2.2.1]heptan-3-one (15 g, 135 mmol) was dissolved inacetonitrile (60 g). The solution was heated to 40-43° C. Seed crystalsof (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt were added. Di-p-toluoyl-L-tartaric acid (10.4 g, 34 mmol)dissolved in acetonitrile (29 g) was added dropwise over a period of2.25 hours. The mixture was cooled to 25° C. The mixture was filteredand the solid was washed with acetonitrile (30 g, 23° C.). The solid wasdried under reduced pressure (60° C.) to give 13.48 grams of product asa white solid. Chiral HPLC: 98.3%(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one.

Example 3 Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one

(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt (14.3 g, 0.047 mol) was placed in tert-butylmethylether (200 g)and extracted with 1 molar aqueous hydrochloric acid solution (130 mL).The aqueous extract was concentrated under reduced pressure at 70° C.Ethyl acetate (30 g) and saturated aqueous potassium carbonate (7 g)were added. The layers were separated and the aqueous layer wasextracted with ethyl acetate (20 g). The two ethyl acetate solution werecombined and the solvent was removed under reduced pressure at 22° C. togive 3.4 g of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. HPLC: (Zorbax300-SCX (MAC-MOD Analytical, Inc., Chadds Ford, Pa.) 0.03 molar KH₂ PO₄(adjusted to pH 2.5 with H₃ PO₄)/methanol, 1:1) purity 96%.

Example 4 Formation of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-D-tartaric acid hemisalt

(±)-1-Azabicyclo[2.2.1]heptan-3-one (15 g, 135 mmol) is dissolved inacetonitrile (approximately 60 g). The solution is heated to 40-43° C.Seed crystals of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-D-tartaric acid hemisalt are added. Di-p-toluoyl-D-tartaricacid (10.4 g, 34 mmol) dissolved in acetonitrile (approximately 29 g) isadded dropwise. The mixture is cooled to 25° C. The mixture is filteredand the solid is washed with acetonitrile. The solid is dried underreduced pressure to give the product as a white solid.

Example 5 Formation of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one

(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt (14.3 g, 0.047 mol) is placed in tert-butylmethylether(approximately 200 g) and extracted with 1 molar aqueous hydrochloricacid solution (approximately 130 mL). The aqueous extract isconcentrated under reduced pressure. Ethyl acetate (approximately 30 g)and saturated aqueous potassium carbonate (approximately 7 g) are added.The layers are separated and the aqueous layer is extracted with ethylacetate (approximately 20 g). The two ethyl acetate solution arecombined and the solvent is removed under reduced pressure to give(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one.

Example 6 Formation of (4R)-1-azabicyclo[2.2.1]heptan-3-one,O-[3-(3-methoxyphenyl)-2-propynyl)oxime

The utility of the resolved hemitartrate salts is illustrated herein.(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt, (4.57 g) and O-(m-methoxyphenylpropargyl)hydroxylamine oxylate(3.26 g) were dissolved in di-methylsulfoxide (DMSO) (20 mL).Triethylamine (7.0 g) was added at 20° C. After 1 day at roomtemperature additional O-(m-methoxyphenylpropargyl)hydroxylamine oxylate(0.56 g) and triethylamine (1.2 g) were added. After an additional 6days at room temperature additionalO-(m-methoxyphenylpropargyl)hydroxylamine oxylate (0.76 g) andtriethylamine (2 g) were added. After 1 day at room temperature themixture was heated to 60-70° C. for 1 hours. The mixture was reduced involume by distillation under reduced pressure until a homogeneoussolution with a weight of approximately 35 g was obtained. The mixturewas combined with water (10 mL), saturated aqueous sodium bicarbonatesolution (30 mL) and tert-butylmethylether (30 mL). The mixture wasfiltered and the phases were separated. The aqueous phase was extractedwith tert-butylmethylether (3×50 mL). The tert-butylmethylether extractswere combined and the solvent was removed under reduced pressure to give(4R)-1-azabicyclo[2.2.1]heptan-3-one,O-[3-(3-methoxyphenyl)-2-propynyl)oxime (4.33 g) as a mixture of E and Zisomers. The oil was dissolved in tert-butylmethylether (25 mL) andextracted with aqueous citric acid (1×20 mL, and 1×10 mL of 0.33 M). Theaqueous extracts were combined and the pH was adjusted to 8.5 withsodium bicarbonate. The aqueous mixture was extracted withtert-butylmethylether (2×25 mL). The tert-butylmethylether extracts werecombined and extracted with water (10 mL). The organic phase wasconcentrated under reduced pressure at 40-48° C. to give 3.52 g of(4R)-1-azabicyclo[2.2.1]heptan-3-one,O-[3-(3-methoxyphenyl)-2-propynyl)oxime. HPLC: (Zorbax SB-CN (MAC-MODAnalytical, Inc., Chadds Ford, Pa.) 0.05 molar triethylamine (adjustedto pH 3 with H₃ PO₄)/acetonitrile/methanol, 8:1:1) purity 98% by area asa 39:61 mixture of E and Z isomers, di-p-toluoyl-L-tartaric acid content<0.05%.

Example 6 illustrates the utility of the respective hemitartrate saltswithout the necessity of first isolating the free base. The product ofExample 6 particularly the Z-isomer, is known to exhibit anti-muscarinicactivity.

By the claim term "substantially one but not both" relative to thecompound pairings(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one/di-p-toluoyl-L-tartaric acid;and (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one/di-p-toluoyl-D-tartaric acidis meant a separable mixture containing predominately one compoundpairing but not the other. The term does not simply mean that theseparable mixture is free of the other compound pairing, but that theother compound pairing, if present, is present in such quantity that itsconcentration will not interfere with obtaining a precipitate which isenriched in the desired di-p-toluoyltartrate hemisalt. The amount of the"non-desired" isomer/di-p-toluoyltartaric acid pairing which istolerable may also be described as a "non-enrichment interferingamount." The term "substantially enantiomerically pure" and similarterms used herein are as understood by one skilled in the art.Substantial enantiomeric purity is preferably greater than 90% purerelative to the isomers in question, more preferably greater than 95%pure, and most preferably greater than 98% pure on this basis.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed is:
 1. A process for the resolution of one desired(1R,4S) or (1S,4R) isomer of (±)-1-azabicyclo[2.2.1]heptan-3-one, saidprocess comprising:a) dissolving a mixture of (1R,4S)- and(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in a selectivecrystallization-effective solvent comprising one or more protic and/oraprotic solvents to form a separable mixture; b) combining with saidseparable mixture a di-p-toluoyltartaric acid isomer such thatsubstantially one but not both of the following pairs of compounds willbe present in said separable mixture:b)I)(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaricacid; or b)ii) (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one anddi-p-toluoyl-d-tartaric acid; c) allowing a precipitate to form andcollecting said solid precipitate from the mother liquid of saidseparable mixture, said precipitate comprising:c)I)(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt; or c)ii) (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-D-tartaric acid hemisalt; wherein a precipitate comprisingc)I) is obtained when said separable mixture comprises b)I) and whereina precipitate comprising c)ii) is obtained when said separable mixturecomprises b)ii).
 2. The process of claim 1 wherein said one desiredisomer is (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, saiddi-p-toluoyltartaric acid is di-p-toluoyl-L-tartaric acid, and saidprecipitate comprises (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-L-tartaric acid hemisalt.
 3. The process of claim 1 whereinsaid one desired isomer is (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, saiddi-p-toluoyltartaric acid is di-p-toluoyl-D-tartaric acid, and saidprecipitate comprises (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one,di-p-toluoyl-D-tartaric acid hemisalt.
 4. The process of claim 2 whereinsaid di-p-toluoyl-L-tartaric acid is combined with said separablemixture in an amount of from about 50% to about 100% of stoichiometrycalculated as the hemisalt from the amount of (1S,4R) isomer containedin said separable mixture.
 5. The process of claim 2 wherein saiddi-p-toluoyl-L-tartaric acid is combined with said separable mixture inan amount of from about 70% to about 90% of stoichiometry calculated asthe hemisalt from the amount of (1S,4R) isomer contained in saidseparable mixture.
 6. The process of claim 3 wherein saiddi-p-toluoyl-D-tartaric acid is combined with said separable mixture inan amount of from about 50% to about 100% of stoichiometry calculated asthe hemisalt from the amount of (1R,4S) isomer contained in saidseparable mixture.
 7. The process of claim 3 wherein saiddi-p-toluoyl-D-tartaric acid is combined with said separable mixture inan amount of from about 70% to about 90% of stoichiometry calculated asthe hemisalt from the amount of (1R,4S) isomer contained in saidseparable mixture.
 8. The process of claim 1 wherein said selectivecrystallization solvent comprises one or more of alcohol solvents, ethersolvents, ester solvents, and nitrile solvents.
 9. The process of claim1 wherein said selective crystallization solvent is selected from thegroup consisting of acetonitrile, ethyl acetate and isopropyl alcohol.10. A process for the resolution of(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, said process comprising:a)dissolving a mixture of (1R,4S)- and(1S,4R)-a-azabicyclo[2.2.1]heptan-3-one in a selectivecrystallization--effective solvent comprising one or more protic and/oraprotic solvents to form a separable mixture; b) combining with saidseparable mixture, di-p-toluoyl-L-tartaric acid; c) allowing aprecipitate to form and collecting said solid precipitate from themother liquid of said separable mixture, said precipitate comprising(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acidhemisalt.
 11. The process of claim 10 wherein saiddi-p-toluoyl-L-tartaric acid is combined with said separable mixture inan amount of from about 50% to about 100% of stoichiometry calculated asthe hemisalt from the amount of (1S,4R) isomer contained in saidseparable mixture.
 12. The process of claim 10 wherein saiddi-p-toluoyl-L-tartaric acid is combined with said separable mixture inan amount of from about 70% to about 90% of stoichiometry calculated asthe hemisalt from the amount of (1S,4R) isomer contained in saidseparable mixture.
 13. A process for the resolution of one(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, said process comprising:a)dissolving a mixture of (1R,4S)- and(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in a selectivecrystallization--effective solvent comprising one or more protic and/oraprotic solvents to form a separable mixture; b) combining with saidseparable mixture di-p-toluoyl-d-tartaric acid; c) allowing aprecipitate to form and collecting said solid precipitate from themother liquid of said separable mixture, said precipitate comprising(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-D-tartaric acidhemisalt.
 14. The process of claim 13 wherein saiddi-p-toluoyl-D-tartaric acid is combined with said separable mixture inan amount of from about 50% to about 100% of stoichiometry calculated asthe hemisalt from the amount of (1R,4S) isomer contained in saidseparable mixture.
 15. The process of claim 13 wherein saiddi-p-toluoyl-D-tartaric acid is combined with said separable mixture inan amount of from about 70% to about 90% of stoichiometry calculated asthe hemisalt from the amount of (1R,4S) isomer contained in saidseparable mixture.
 16. A composition comprising the compound: ##STR5##17. A composition comprising the compound:
 18. A composition comprisinga hydrate, solvate or mixture thereof of the compound of claim
 16. 19. Acomposition comprising a hydrate, solvate or mixture thereof of thecompound of claim 17.